Distinguishing Pathogens from Self

The cells of the innate immune system, particularly specialized phagocytes such as dendritic cells (DCs) and macrophages, represent a ‘first line’ of surveillance and defense against infection. Major advances over the past 20 years have led to the identification of an armory of receptors that recognize common microbial components and stimulate cytokine release, which in turn promote adaptive immune responses.

However, many of these microbial components are shared by innocuous or commensal microbes that are present in large numbers in the intestine and other sites in the body. Furthermore, it is now clear that these same receptors can be triggered by self-derived macromolecules, such as nucleic acids, lipids, and polysaccharides. We believe that inappropriate activation of the innate immune system by self-associated components may be a major driving force behind many autoimmune or chronic inflammatory diseases. Research in the lab is directed at understanding how innate immune cells recognize and distinguish self from pathogens, and respond accordingly.

A major focus of the laboratory’s work in this area is the recognition of cells that die by apoptosis or other mechanisms. Apoptosis is a ‘silent’ form of cell death, used for removal of cells that are damaged or no longer needed. Cells that initiate apoptosis are rapidly removed by phagocytes or neighboring cells. The lab team has shown that when dendritic cells phagocytose apoptotic cells, they adopt a ‘regulatory’ phenotype that promotes immune tolerance. Researchers believe that this mechanism allows the immune system to constantly survey self antigens and maintain immune tolerance. Our current research is focused on understanding how recognition of apoptotic cells modifies innate immune signaling to promote immune tolerance, and how defects in this process may lead to autoimmune diseases such as systemic lupus erythematosus (SLE).

Finding out how innate immune cells recognize potential targets and respond appropriately is essential to the understanding of both defense against infection and autoimmunity.